The program that I established for NF1-related tumors focuses on the clinical application of new molecularly targeted anticancer drugs to these tumors based on the mechanism of action of the drug and the known pathogenesis of these tumor (e.g., the NF1 gene product, neurofibromin, regulates Ras activity through its GTPase-related domain and lack of functional neurofibromin leads to dysregulated Ras and tumorigenesis). The agents being studied include the farnesyltransferase inhibitor, tipifarnib (I am leading the first multi-institutional phase II trial of a targeted therapy for NF1 funded by a US Army Clinical Trial Award), which was designed to target Ras, the anti-fibrotic agent, pirfenidone, the Raf kinase and angiogenesis inhibitor, sorafenib, and the mTOR inhibitor sirolimus. As part of establishing the NF1 program, I have also focused on developing new, more sensitive clinical trial endpoints to assess the size and growth rate of NF1-related tumors, such as our automated volumetric MRI method, which has become the primary method of measuring drug effect for NF1 clinical trials. I have also developed new clinical trial designs that account for the poorly understood natural history of NF1-related tumors and their slow and unpredictable growth. The absence of an established infrastructure for the conduct of NF1 clinical trials required the development of collaborations and funding prior to the initiation of multi-institutional clinical trials. In addition to coordinating 4 multi-institutional clinical trials of new agents in children with plexiform neurofibromas (PN), I have also played a leadership role in the development of a new DoD-funded national NF1 Clinical Trials Consortium. The automated volumetric MRI method of measuring PN, which is used in our multi-institutional clinical trials has not only allowed us to reproducibly and sensitively measure changes in PN size and accurately define time to disease progression as primary trial endpoint, but it has also improved our understanding of the natural history of these tumors. We demonstrated with this method that PN growth rate is highly age-dependent and that the rate of growth within patients is uniform over the 18 to 30 months required to assess the effect of a new drug treatment. In collaboration with NHGRI, I am also studying the natural history of dermal neurofibromas and developing endpoints for future clinical trials by applying digital technology to assess lesion volume. For the molecularly targeted agents, such as tipifarnib and sorafenib, I perform the phase I and II clinical trials in children with cancer prior to initiating the NF1 trials. I plan to expand this approach I have taken to other genetic tumor predisposition syndromes including neurofibromatosis type 2 related tumors.